Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved pharmacological treatments. Therefore, there is a clear need to identify and develop novel pharmacotherapies for cocaine craving and relapse. The neurobiological mechanisms underlying drug taking overlap, to some degree, with those of food seeking. We have recently shown that intake of highly palatable food is attenuated by glucagon-like peptide-1 (GLP-1) receptor activation in the brain. Specifically, stimulation of GLP-1 receptors in the mesolimbic dopamine system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), reduced intake of highly palatable food. In light of an extensive literature indicating that the VTA and NAc play a critical role in cocaine addiction, these results suggest that activation of central GLP-1 receptors may also prevent cocaine taking and seeking in rats. However, no studies, to date, have examined the role of central GLP-1 receptors in drug addiction. The proposed research focuses on identifying the role of central GLP-1 receptors in animal models of cocaine addiction. Our preliminary findings indicate that administration of a GLP-1 receptor agonist directly into the VTA or NAc attenuates cocaine self-administration and the reinstatement of cocaine-seeking behavior, an animal model of drug craving and relapse. These exciting results suggest that GLP-1 ligands, which are currently FDA-approved for treating type II diabetes, could be used to treat cocaine dependence. In addition to using these two animal models of cocaine addiction to screen the efficacy of GLP-1 receptor ligands to attenuate cocaine taking and seeking (Aim 1), we will determine the physiological relevance of endogenous VTA and NAc GLP-1 signaling in cocaine taking and seeking. Using a GLP-1 receptor antagonist and our recently developed shRNA construct, we will reduce endogenous GLP-1 receptor signaling in the VTA or NAc prior to cocaine self-administration and reinstatement tests (Aim 2). We predict that pharmacological inhibition and viral-mediated down-regulation of GLP-1 receptor expression in the VTA and NAc will augment cocaine self-administration and cocaine priming-induced reinstatement of cocaine seeking. Central GLP-1-producing neurons are located almost exclusively in the nucleus tractus solitarius (NTS) of the caudal brainstem and we have recently shown that these neurons have direct, monosynaptic connections with the VTA and NAc. In order to determine if cocaine exposure activates NTS GLP-1-producing neurons that project to the VTA or NAc, we will inject the retrograde tracer FluoroGold into the VTA or NAc during cocaine self-administration and prior to cocaine priming-induced reinstatement (Aim 3). Using antibodies for FluoroGold, the activity-dependent immediate early gene c-fos, and preproglucagon (PPG), the gene encoding GLP-1, we will determine whether cocaine exposure activates NTS PPG-expressing neurons that project to the VTA or NAc. The mechanisms by which cocaine activates NTS PPG-expressing neurons are not clear. Cocaine taking is associated with elevated plasma corticosterone levels and our preliminary data indicate that peripheral corticosterone administration increases activation of PPG-expressing neurons in the NTS. Therefore, we will investigate whether corticosterone administration directly into the NTS is sufficient to attenuate cocaine taking and seeking, and whether these effects are blocked by pharmacological inhibition of GLP-1 receptors in the VTA or NAc. Overall, the research proposed in this application will provide strong rationale for re-purposing GLP-1 receptor ligands for the treatment of cocaine addiction and advance a novel framework for the development of efficacious pharmacotherapies for cocaine dependence based on enhanced GLP-1 signaling in the brain.